Technical Field
The present invention relates to the field of medicinal chemistry and pharmacotherapeutics, in particular to a class of fluorosubstituted cyclic amine compounds, preparation thereof, pharmaceutical compositions containing such compounds, and uses thereof as acetylcholinesterase inhibitor, particularly for preparing medicaments for the treatment of Alzheimer's disease, Parkinson's disease, epilepsy or schizophrenia.
Background Art
With the rapid aging of society, the health status of the aged has received an increasing attention. Among numerous diseases that threaten the health of the aged, Alzheimer's disease (AD), also known as senile dementia, is the most common cause of dementia in the aged. AD is a progressive fatal neurodegenerative disease, the clinical manifestations of which are worsening of cognitive and memory functions, progressive decline of activities of daily life and a variety of neuropsychiatric symptoms and behavioral disorders. Incidence of AD in the aged is very high: nearly 50% of people affected by dementia suffer from Alzheimer's disease. When the patients are older than 85, the proportion will increase to 70%. Among the cause of death in the aged, AD ranks 4th, and lower than cardiovascular, cancer and cerebral apoplexy. Therefore, the study on the medicaments for treating AD has become one of the hotspots of new drug developments.
Reports from IMS Health (ims health) showed that, among the top 500 best-selling drugs in the world's seven major pharmaceutical markets, anti-senile dementia drug market has reached $ 6.41 billion in 2007 which is increased by 24.18% compared with the previous year. In 2008, anti-senile dementia drug market achieved an increase of 12.49% compared with the previous year and the market size reached $7.211 billion. The average annual growth rate of the last three years was about 23% and much higher than the average annual growth of global pharmaceutical market which is 5%-6%. “World Alzheimer Report 2010” showed that the total cost for the treatment of dementia reached $604 billion.
Thus, the anti-senile dementia drug market has great potential. However, “World Alzheimer Report 2011” published in 2012 showed that about 36 million people suffered from dementia, in which as many as three-quarters of patients were undiagnosed and unable to obtain the relevant treatment and care. In high-income countries, only 20-50% of dementia cases obtained primary care while only 10% in low and middle income countries.
At present, the medicaments for the treatment of senile dementia are as follows: (1) cholinesterase inhibitors: such as tacrine, donepezil, Huperzine A, galantamine, etc., a major cause of Alzheimer's Disease is the lack of choline thereby resulting in patients hypomnesia, disorientation, behavioral and personality changes, and so on. Therefore, the medicaments enhancing cholinergic effect play an important role in the treatment of senile dementia. (2) calcium antagonists: such as nimodipine, flunarizine hydrochloride and so on. (3) brain metabolism regulators: such as Nicergoline, Almitrine, piracetam and so on. (4) neuroprotective agents: such as cerebrolysin. Among the clinical medicaments for the treatment of senile dementia, acetylcholinesterase inhibitors (AchEI) with the accurate efficacy are widely used in clinical treatment.
Cholinesterase is a key enzyme in the biological nerve conduction. According to the specificity to catalyzed substrates, cholinesterase is divided into acetylcholinesterase (AChE) and butyrylcholinesterase. Acetylcholinesterase can catalyze the decomposition reaction of acetylcholine, thereby resulting in lack of acetylcholine and the failure of neural signal conduction and further leading to the decline of patients' cognitive function and loss of memory, and clinical manifestations are senile dementia symptoms. Acetylcholinesterase inhibitors can inhibit AChE activity, slow down the rate of hydrolysis of acetylcholine, improve the level of acetylcholine in the synaptic cleft and ensure the normal conduction of neural signals thereby playing a therapeutic effect on senile dementia.
Donepezil hydrochloride (E2020) disclosed in EP0296560A2 is the second generation acetylcholinesterase inhibitor, the treatment effect of which is reversible inhibition of acetylcholine hydrolysis caused by acetylcholinesterase (AChE) thereby increasing the acetylcholine content in receptor site. E2020, which was the second medicament approved by US FDA for the treatment of mild and moderate senile dementia, was developed by Eisai and Pfizer Limited and come into the market in 1997 in United States. E2020, which has been approved for marketing by more than 50 countries and regions including China, is a relatively safe and effective drug for the treatment of senile dementia and the preferred drug for treating mild and moderate senile dementia. The selective affinity of donepezil hydrochloride for acetylcholinesterase is 1250 times stronger than that for butyrylcholinesterase. Donepezil hydrochloride can obviously inhibit the cholinesterase in brain while butyrylcholinesterase mainly exists outside of the central nervous system. So E2020 has no effect on peripheral heart (myocardium) or the small intestine (smooth muscle) and has few side effects. Compared with tacrine, E2020 has better effects, higher selectivity and less toxicity for central nervous system. Therefore, E2020 has become first-line medicament for treating senile dementia in clinical and the global sales in 2010 reached $3.4 billion.
However, there is still a large gap between the overall development speed of anti-AD medicament studies and the market demand, and there are few of medicaments with confirmative efficacy. Medicaments on the market can not meet the needs of the patients. Therefore, more acetylcholinesterase inhibitors are needed to meet the market demand.